Rational combinations of radiation and chemotherapy which enhance tumor response but minimize normal tissue damage have not been derived clinically because of lack of experimental data. A limited number of empirical successful treatments have evolved using primarily very effective single and multiagent chemotherapy simultaneously with radiation. The timing of chemotherapy relative to radiation is extremely important in this interaction and this timing is being studied at intervals from plus 64 to minus 64 hours relative to radiation. Studies are being conducted in mouse normal tissue systems, including bone marrow, intestinal crypt cells, lungs, esophagus and, in the near future, brain and kidney. Studies are also being conducted in five mouse model tumor systems that have recently been acquired and developed in our laboratory. These systems are for in vivo/vitro cell survival assays as well as in vivo response criteria. Additional studies are evaluating the effects of drugs and radiation on immuno-competent t-cells. The maximum effect is being determined as a function of time, drug dose, radiation dose and time interval between the two modalities. The comparable values for tumor and normal tissue will be used to determine strategies for optimum improvement in the therapeutic ratio.